The effective long-term use of medicines is limited, among other reasons, by frequent administration of the medicine and a resulting problem of compliance by the patient. The use of medicaments in dosages taken one or several times daily for months or years, in the long run, leads to an uncertain intake and, consequently, to variable effectiveness.
A medicine which is only absorbed to a small extent when administered orally or through the skin or mucous membrane must be injected. The daily injection of a medical product over a long term is unpleasant for the patient since it is often painful.
Further, there is a large number of medical products which decompose in the injected area and are metabolized with a resulting pharmacokinetic profile which is unsatisfactory.
Medical compositions have been disclosed in the literature consisting of a medically active substance incorporated into a polymer matrix from which the medicine is gradually released. These medicine-embedded compositions can either be injectable or implantable-type medicines. Thus, for example, the DE-OS 3 428 372 describes the impregnating or embedding of pharmaceutically active peptides in poly D(-)-3-hydroxy butyric acid, and the EP-OS-0 052 510 describes the impregnating or embedding of luteinizing hormone-releasing hormone in polymeric materials as, for example, poly-lactic acid or poly-lactic acid/poly-glycol acid copolymers.
When administered into a patient's body by subcutaneous injection or implantation, the medically impregnated polymer slowly dissolves and releases the medically active substance over several days or even months. The frequency of injection of such compositions can be reduced drastically and consequently patient compliance, as well as the effectiveness of the medicine, can be increased.
The manufacture of such gradually released medical compositions can be achieved by methods disclosed in the literature, including:
Micro-Encapsulation with Organic Solvents (L. M. Sanders et al., J. Contr. Release 2(1985) 187 or P. B. Deasy, Microencapsulation and Related Drug Processes, M. Dekker, Inc., New York, 1984); PA1 Emulsification and Subsequent Vaporization of Solvent Means (T. R. Tice & R. M. Gilley, J. Contr. Release, 2 (1985) 343; PA1 Spray Drying (D. L. Wise et al., Life Science, 19 (1976) 867); PA1 Extrusion (A. J. Schwope et al, Life Science, 17 (1975) 1877); PA1 Fusible Embedding (A. J. Schwope et al, Life Science, 17 (1975) 1877); and PA1 Boundary Surface Polymerization (G. Birrenbach & P. Speiser, J. Pharm. Science, 65 (1976) 1763). PA1 Bacillus subtilis spores PA1 Bacillus stearothermophilus PA1 Escherichia coli PA1 Salmonella edinburgh PA1 Staphylococcus aureus PA1 Pseudomonas aeruginosa PA1 Candida albicans PA1 Aspergillus niger
The methods disclosed in the cited literature, however, have either the disadvantage that they require use of large amounts of toxic organic solvents whereby the resulting polymer embedded compositions have high solvent residue concentrations, as see J. P. Benoit et al, Int. J. Pharmaceutics, 29 (1986) 95, or the methods require use of high temperatures or pressures, which lead particularly to high local temperature increases which can damage the embedded medicines, as see L. M. Sanders et al, J. Pharm. Science 75 (1986) 356. If the medical composition remains under the skin or bodily tissue for a long period of time, local toxic tissue reactions can be expected from the organic solvents. For this reason, the amount of solvent residue in the product has to be reduced as completely as possible.
In addition to the solvents in the polymer matrix, one finds that approximately 1 to 2% of the dispersing solvent has been absorbed at the surface of micro particles manufactured by the emulsion method. The solvent cannot be removed by a washing process. As a rule, silicon oil or another lipophilic liquid is used which has the disadvantage of not being degradable by the patient's body, as see EP-OS-81 305 426.9.
Further, all micro-particles (for example, nano capsules) manufactured by polymerization contain mono-, di- and oligomers in the polymer matrix, and often polymerization initiator molecules as well. All of these substances bestow on the micro-particles toxicological characteristics which must be regarded as considerably worse.
Boundary surface polymerization as well as the emulsion procedures have not been successfully transferred from a small scale technical method to a full scale manufacturing operation or production so that commercial introduction of respective products or preparations has not taken place and the so-called nano capsule patent teaching (Speiser DE 296 5725) has not changed this.
Finally, many methods which use organic solvents do not operate in closed systems. Thus, the burden on the environment is considerable. The necessary purification of the air by means of recovery plants is expensive and becomes problematical technically with large throughput as is customary with spray drying.
An essential requirement of the above-described medicine embedded compositions is the sterility of the products. The methods mentioned above do not per se result in sterile products. Either the entire manufacturing process must be carried out under sterile or aseptic conditions with great expense or the product must be sterilized after its manufacture. At present, post-sterilization by means of gamma rays is customary. Apart from governmental regulations which place strict conditions on the marketing of products which have been sterilized with gamma rays this type of sterilization damages the medical ingredient, in particular, if the product contains a peptide medication. The polymer matrix as well, for example the poly-lactic acid, can be decomposed by gamma rays. Thus, release of the medical ingredient from the product or the solubility characteristics of the medical ingredient can change uncontrollably, as see L. T. Sanders et al., J. Contr. Release, 2 (1985) 187.